Field of the Invention
The invention in the field of biochemistry and medicine relates to a method testing pleural fluid samples in conjunction with fibrinolytic therapy.
Description of the Background Art
Approximately 65,000 patients in the United States alone develop empyema (EMP) or related complicated parapneumonic pleural effusions annually. The incidence of EMP is increasing worldwide. EMP is associated with serious morbidity, a mortality of about 20%, and patient care costs of roughly $500 million per year (Burgos, J et al. Curr. Opin. Pulm. Med. 19:350-356 (2013); Grijalva, C G et al. Thorax 66:663-668 (23011); Hendrickson, D J et al. Pediatr. Infect. Dis. J. 27:1030-1032 (2008); Maskell, N A et al. N. Engl. J. Med. 352:865-874 (2005); Bender, J M et al. Emerg. Infect. Dis. 15:44-48 (2009))
Intrapleural fibrinolytic therapy (IPFT) has been used for over 60 years to expedite pleural drainage and prevent lung restriction, but its efficacy and safety profile, especially in adults, remains uncertain. Bleeding occurs in up to 15% of patients. Current IPFT protocols use empirically dosed, off-label interventions and reflect rudimentary knowledge about the regulation of IPFT in EMP and its pathogenesis (Krishnan, S et al., Chest 112:1579-83 (1997); Kornecki, A et al. J. Pediatr. Surg. 32:1473-15. (1997); Handman, H. P et al. Pediatr. Infect. Dis. J. 12:958-59 (1993); de Benedictis, F M et al. Pediatr. Pulmonol. 29:438-42 (2000); Barbato, A et al. Pediatr. Pulmonol. 35:50-65 (2003); Stringel, G et al. J. Pediatr. Surg. 29:1539-40 (1994); Sonnappa, S et al. Am. J. Respir. Crit Care Med. 174:221-27 (2006); Sonnappa, S et al. Paediatr. Respir. Rev. 8:164-70 (2007); Barnes, N P et al. Pediatr. Pulmonol. 39:127-34 (2005); Thomson, A H et al. Thorax. 57:343-47 (2002); Stefanutti, G et al. Surgery 148:589-94 (2010). The present invention is project is designed to address these critical gaps which have slowed the progress in the field and fostered empiric approaches to the use of IPFT Corcoran, J P et al. Chest 145:14-17 (2014); Colice, G L and Idell, S Chest 145:17-20 (2014); Colice, G L and Idell, S 2014. Response. Chest 146:e104-105 (2014)
The present inventors and their colleagues identified and validated active plasminogen activator inhibitor 1 (PAI-1) as a biomarker and therapeutic target for IPFT in pleural injury. Karandashova, S et al. Am. J. Respir. Cell Mol. Biol. 48:44-52 (2013); Komissarov, A A et al. Am. J. Physiol Lung Cell Mol. Physiol 305:L682-92 (2013)) Three mechanistically different forms of PAI-1 targeted IPFT are effective in reversing tetracycline-induced pleural organization in rabbits. These interventions allow the use much lower doses of fibrinolysin for therapy—up to 8-fold decreased, and otherwise ineffective, doses. This mitigates bleeding risk.
There is no clinically tractable testing currently available to guide delivery of intrapleural fibrinolytic therapy or to predict its outcomes, so that this test advances this medical management problem. The present inventors designed a companion diagnostic test; the Fibrinolytic Potential Assay (FPA), the subject of this application, to monitor outcomes of PAI-1 targeted or other forms of IPFT. This invention prediction of outcomes of intrapleural fibrinolytic therapy, how to dose the intervention and when to give it. No such test is currently available and current fibrinolytic therapy yields unpredictable outcomes as dosing is currently completely empiric, which may compromise efficacy and safety.